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PMID: 18391074 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells.

The Journal of cell biology ·Vol. 181 ·No. 1 ·2008-04-07 ·Pages 131-41

Kawasaki K, Watabe T, Sase H, Hirashima M, Koide H, Morishita Y, Yuki K, Sasaoka T, Suda T, Katsuki M, Miyazono K, Miyazawa K

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell-derived VEGFR2(+) mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)-BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A-induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras(-/-) mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2(+) progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2(+) progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6-9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras-Erk signaling to direct endothelial specification of VEGFR2(+) vascular progenitor cells.

MeSH Terms
Animals Cell Differentiation/drug effects Embryo, Mammalian/cytology Embryonic Stem Cells/cytology Endothelial Cells/cytology Enzyme Inhibitors/pharmacology Methionine/analogs & derivatives,pharmacology Mice Mice, Inbred C57BL Platelet Endothelial Cell Adhesion Molecule-1/metabolism Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors,metabolism Signal Transduction Vascular Endothelial Growth Factor A/metabolism Vascular Endothelial Growth Factor Receptor-2/metabolism
Chemicals
Enzyme Inhibitors FTI 277 Platelet Endothelial Cell Adhesion Molecule-1 Vascular Endothelial Growth Factor A Methionine Vascular Endothelial Growth Factor Receptor-2 Hras protein, mouse Proto-Oncogene Proteins p21(ras)
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Kawasaki Kyoko
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-0033, Japan.
Watabe Tetsuro
Sase Hitoshi
Hirashima Masanori
Koide Hiroshi
Morishita Yasuyuki
Yuki Keiko
Sasaoka Toshikuni
Suda Toshio
Katsuki Motoya
Miyazono Kohei
Miyazawa Keiji
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200709127
Published
2008-04-07
Pages
131-41
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2287293
Subset
IM
External Links
PubMed source DOI: 10.1083/jcb.200709127 PMC Full Text View journal details
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